Respiratory Syncytial Virus

Abstract

Human respiratory syncytial virus (hRSV) is the leading cause of acute lower respiratory infections in infants and young children worldwide. Epithelial cells lining the nasal passages and respiratory tract are the primary target of hRSV infection. Replication of hRSV in the host cell follows the general strategy of the Mononegavirales. Cells respond to hRSV infection by producing a variety of cytokines, chemokines and interferons that are involved in the host inflammatory response. Although primary hRSV infection occurs at an early age, immunity is short‐lived or incomplete and reinfections occur throughout life. In fact, hRSV is also a pathogen of major importance for the elderly and immunocompromised adults. Initial efforts to develop a vaccine based on formalin‐inactivated virus resulted in vaccine‐enhanced disease after natural infection. However, recent advances on hRSV immunobiology have brought effective vaccines and antivirals as realistic objectives in a foreseeable future.

Key Concepts

  • Human respiratory syncytial virus (hRSV) is the leading cause of serious respiratory tract disease in children and infants worldwide but also a pathogen of recognised importance in the elderly and immunocompromised adults.
  • hRSV belongs to the Orthopneumovirus genus of the Pneumoviridae family within the Mononegavirales order of negative‐strand RNA viruses.
  • The hRSV genome comprises 10 genes that encode 11 viral proteins.
  • hRSV derives its name from the formation of multinucleated, fused cells (syncytia), which are the hallmark of infection of cultured cells or lung tissue.
  • Following attachment to the target cell, entry by hRSV is mediated by fusion of the viral envelope with the host cell plasma membrane at neutral pH.
  • The entire replication cycle of hRSV takes place in the cytoplasm of the infected cell.
  • Reverse genetics has permitted the recovery of infectious hRSV from complementary DNA.
  • hRSV strains disseminate rapidly worldwide, accumulating mutations predominantly in the attachment protein.
  • Pathology associated with hRSV infections is not only the result of direct virus injury, but largely the consequence of an aberrant immune/inflammatory response.
  • Palivizumab, a neutralising monoclonal antibody directed against the hRSV fusion protein, is the only product available in the market for specific prophylactic treatment of children at high risk of severe infection.

Keywords: negative‐strand RNA viruses; family Pneumoviridae; bronchiolitis; membrane fusion; pathogenesis; vaccines; antivirals

Figure 1. Paramyxovirus and pneumovirus genome organisation. Gene maps for representative members of each genus of the Paramyxoviridae and Pneumoviridae families are shown. The nucleotide length of each viral genome (nt), the intergenic regions and the noncoding termini (not to scale) are shown. Genes are colour‐coded for function and the overlap between the hRSV M2 and L genes is indicated.
Figure 2. Human respiratory syncytial virus structure. (a) Negative‐stained preparation of partially purified hRSV (A2 strain). Electron micrograph by Lesley Calder, Crick Institute, London, UK, reproduced at a magnification of 90 000×. (b) Schematic diagram of the hRSV virion (not to scale). The colour coding of proteins matches that of Figure.
Figure 3. Human respiratory syncytial virus G glycoprotein. The full‐length, 298 amino acid membrane‐anchored G protein (Gm) and the 233 amino acid soluble G protein (Gs) are shown (long strain). Gs is formed by alternative translation initiation at M48 in the middle of the transmembrane region (thick solid line), followed by cleavage with about the same efficiency after either residue 65 or residue 74 (only the second form is shown). Inverted triangles represent N‐glycosylation sites and vertical lines indicate O‐linked glycosylation sites. Cysteine residues overlapping the central conserved domain are represented by solid circles. The lower part of the figure depicts a model of the three‐dimensional structure of Gm. Although Gm is probably tetrameric, a dimer is shown for simplicity. Antibody epitopes and the glycosaminoglycan (GAG)‐binding site are indicated by arrows. Reproduced form Melero 2006 © Elsevier.
Figure 4. Human respiratory syncytial virus fusion (F) glycoprotein. (a) The primary structure is represented, denoting the hydrophobic signal peptide (SP), the fusion peptide (FP) and the transmembrane (TM) regions as hatched boxes. The arrows indicate the double cleavage sites of F0 that yield disulfide‐linked (S–S) F2 (black) and F1 (red) chains. Heptad repeat sequences HRA and HRB are shown in green and blue colour, respectively. Surface representation of the three‐dimensional structures of the trimeric F protein folded in the prefusion (b) and postfusion (c) conformations. The three protomers are represented, one of them in darker shades for better visualisation. The locations of different antigenic sites (Ø and I–V) are delineated with different colours and their correspondence in the two structures indicated by arrows. Note that antigenic sites Ø, III and V are not present in the postfusion conformation (c). The 6‐helix bundle (6HB) motif is exclusive of the postfusion conformation (c). Antibodies specific to the 6HB have been obtained upon immunisation of mice with designed peptides.
Figure 5. Diagram of the hRSV infectious cycle. The different steps of infection of a single cell by hRSV are illustrated.
Figure 6. Global distribution of viruses belonging to the BA genotype with a 60 nucleotide duplication in the G protein gene. Different lineages are colour‐coded and for each lineage the years of circulation are shown on the right. Reproduced from Trento et al. 2010. © American Society of Microbiology.
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Further Reading

Collins PL and Graham BS (2008) Viral and host factors in human respiratory syncytial virus pathogenesis. Journal of Virology 82: 2040–2055.

Collins PL and Melero JA (2011) Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Research 162: 80–99.

Collins PL, Fearns R and Graham BS (2013) Respiratory syncytial virus: virology, reverse genetics, and pathogenesis of disease. Current Topics in Microbiology and Immunology 372: 3–38.

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Graham BS and Anderson LJ (2013) Challenges and opportunities for respiratory syncytial virus vaccines. Current Topics in Microbiology and Immunology 372: 391–404.

Mejias A and Ramilo O (2015) New options in the treatment of respiratory syncytial virus disease. Journal of Infection 71 (Supplement 1): S80–S87.

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Melero, José A, Trento, Alfonsina, and Mas, Vicente(Nov 2017) Respiratory Syncytial Virus. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000429.pub4]